In 2011, the Apicomplexan Molecular Physiology Section made a fundamental contribution to understanding the molecular basis of increased erythrocyte permeability after infection with malaria parasites. Altered host cell permeability has been known for several decades, with various groups documenting the range of organic and inorganic solutes with increased uptake. Over the past ten years, patch-clamp studies from our group and from others determined that increased uptake results from the action of one or more ion channels. However, both the number of distinct ion channels and whether they are of host or parasite origin have been intensely debated. We have now addresses these questions by using a high-throughput inhibitor screen to find an isolate-specific PSAC antagonist (ISPA-28) that specifically blocks sorbitol uptake into red cells infected with the Dd2 parasite line;cells infected with the HB3 parasite line have channels that are blocked 800-fold less effectively. Transport studies with ISPA-28 revealed parallel differences in the ability to block uptake of sugars, amino acids, organic cations, and anions, indicating that a single shared ion channel mediates the uptake of these diverse solutes. Patch-clamp studies implicated PSAC as this shared ion channel. We then used a Dd2 x HB3 genetic cross generated by Dr. Thomas Wellems to track inheritance of ISPA-28 affinity. Our studies indicated relatively simple inheritance with most progeny clones expressing channels identical to one of the two parental lines. We then used QTL analysis with known microsatellite inheritance patterns to map ISPA-28 block to a single locus on the parasites chromosome 3. 15 genes from this locus were selected for DNA transfection experiments into malaria parasites to explore possible functional contributions to PSAC activity. piggyBac-mediated complementation and allelic exchange transfections implicated two related genes from the locus;these genes, known as clag3 genes, were previously thought to play roles in cytoadherence or invasion. We found that these genes undergo expression switching and used in vitro selections to identify parasites that express one or the other allele. These selections confirmed a role in PSAC formation and determined that ISPA-28 binds at a variable domain near the C-terminus of the channel protein. We also raised specific antibodies and used protease susceptibility to localize the protein to the host membrane, as required by functional studies of PSAC. Finally, a recently generated PSAC mutant was found to have a point mutation within a predicted transmembrane domain of the clag3 product, further supporting a central role of clag3 genes in formation of PSAC. Consistent with strict conservation of PSAC activity, the clag gene family is conserved in all rodent, avian and primate malaria species studied to date. As suggested by functional studies, this ion channel appears to serve an essential role for the intracellular parasite. Identification of the responsible genes provides a definitive target for therapeutic intervention against malaria.